Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
  • C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the invention relates to novel aminoacridine- ⁇ , ⁇ -(D)- or -(L)-N-glycoside derivatives, the salts thereof and a chemically unique process for the preparation of such compounds and salts.
• a -p is an anion, preferably halogenide
• R is hydrogen or, a group of the formula II ##STR4## wherein R 1 is hydrogen or a methyl group and
• R 2 is hydrogen or a sugar residue
• X and X' are identical or different and stand for hydrogen, a group of the formula II dimethylamino, halogen, a C 1-4 alkyl group, a C 1-4 alkoxy group, for a nitro-, cyano-, carbomethoxy-, carbamoyl-, phenyl- or a C 1-4 alkyl phenyl group, and
• R 3 is hydrogen or a C 1-5 alkyl group, with the restriction that at least one of the substituents R, X and X' represents a group of the formula -NR 1 R 2 wherein R 2 is a sugar residue.
• the possible sugar residues in group II are as follows: D-glucosyl-, D-galactosyl-, D-mannosyl-, D-xylosyl-, D- and L-arabinosyl-, D-ribosyl-, 6-desoxy-D-glucosyl-, 6-desoxy-D-galactosyl-, L-rhamnosyl-, 2-desoxy-D-arabinosyl-, 2-acetoamido-2-desoxy-D-glucosyl-, daunosaminyl-, maltosyl-, cellobiosyl-, lactosyl-, gentiobiosyl- or laminaribiosylgroup.
• aminoacridines are the most important and most interesting acridine derivatives.
• the attention paid to the aminoacridines cannot only be attributed to the fact that they possess a broader spectrum of physical and chemical properties than any other acridine group but also to the fact that most of the acridine medicaments and -colorants belong to this group (A. Albert, The Acridines, 2nd Edition, Arnold, London; Acheson, R. M. (ed.) (1973), ACRIDINES 2nd Edn., J. Wiley and Sons Inc. New York; A, Albert: Selective Toxicity, 5th Edn., Chapman and Hall, London, 1973; A. Nasim and T. Brychy: Genetic Effects of Acridine Compounds, Mutation Research 65, 261-288 (1979); Quinacridine and Other Acridines in Antibiotics Vol. III, 203-233, Springer-Verlag, Berlin).
• the two aminoacridines proflavine (3,6-diaminoacridine) and acriflavine (3,6-diamino-10-methyl-acridine, 10-methylproflavine) are e.g. known which exert a certain antimicrobial effect.
• the compounds known from these literature sources are toxic and unstable, in an aqueous medium they decompose to the biologically inactive 1-nitroacridone. Furthermore it is disadvantageous that the solutions of the compounds have a pH-value of about 4 what can lead to inflammation at the locus of injection when they are administered as injection. The compounds show also a negative effect on the digestive tract, they cause e.g. nauses and vomitus.
• aminoacridine- ⁇ , ⁇ -(D)- or -(L)-N-glycoside derivatives of the formula I wherein R, R 3 and X are as defined above are prepared by reacting a compound of the formula III, ##STR5## wherein Z is an amino-, methylamino- or dimethylamino group or hydrogen,
• R 3 is as defined above, and the two substituents
• Y and Y' are identical or different and stand for hydrogen, an amino-, methylamino- or dimethylamino group or for halogen, a C 1-4 alkyl or alkoxy group, a nitro-, cyno, carbomethoxy-, carbamoyl-, phenyl- or C 1-4 alkylphenyl group,
• At least one of the substituents Z, Y and Y represents a free or monosubstituted amino group, or the acid addition salts thereof with hexoses, pentoses, desoxy-, desoxyamino-, N-acetyl-hexoses, -pentoses and/or N-methylated aminosugars, isolating the reaction product, optionally acetylating the sugar residue, optionally separating the mono-, di- and triglycosides from each other, optionally reacting the monoglycosides to di- or triglycosides in the described way and optionally forming salts from the obtained compounds of the formula I.
• reaction it is suitable to carry out the reaction in the presence of an acidic catalyst.
• acidic catalyst e.g. hydrochloric acid is suitable.
• reaction is carried out at a temperature of 20°-95° C.
• reaction medium acetone containing water proved to be especially suitable.
• reaction products are separated and purified in a way known per se.
• purification the products are washed, optionally recrystallized or submitted to column chromatography, too.
• silica gel is preferably used and the elution takes place with a mixture of acetone and ammonia.
• 3,6-diamino-acridine and 3,6-diamino-10-methyl-acridine are efficacious in concentrations of 50 ⁇ g/ml against microorganisme (Bacillus subtilis, Salmonalla typhy-murium, Proteus vulgaris, Escherichia coli, Shigella flexneri etc.) while the diglucoside of the 3,6-diamino-acridine is inefficacious also in concentrations of 500 ⁇ g/ml against the named microorganisms.
• aminoacridines are inefficacious against fungi while the diglucoside of 3,6-diamino-10-methyl-acridine is efficacious e.g. against Aspergillus funigatus and Aspergillus niger.
• the acridine-N-glycosides of the invention are free of unpleasant properties which are characteristic of the starting substances containing no sugar residues. Due to their antitumor effect the compounds according to the invention can be used as therapeutica against tumor diseases.
• a test with the Ehrlich-carcinoma was carried out with 50 mice each as test group and as K control group.
• the animals were intraperitoneally infected with 5 ⁇ 10 6 cells each of the ascites tumor according to Ehrlich.
• On the first, second and third day after the infection half of the mice were treated with 12.5 mg/kg.d of 10-methyl-proflavine-diglucoside. The results are summarized in the following table.
• the precipitate is dissolved in 250 ml of water and the solution is admixed with 2 l of acetone.
• the liquid phase isolated from precipitate according to Example 1 contains besides unreacted starting substance and little diglucoside also the monoglucoside.
• the solution is evaporated in vacuo.
• 15 g of evaporation residue 3 g are applied onto a column with a diameter of 7 cm and a height of 25 cm which is filled with 300 g of silica gel G and they are eluted with a mixture of acetone and ammonium hydroxide in a ratio of 65:35.
• Fractions of 10 ml each are collected the composition of which is controlled by thin layer chromatography. For this the same solvent mixture is used as for the column chromatography.
• the fractions containing the monoglucoside are united and evaporated in vacuo.
• the residue is processed with 50 ml of ethylacetate and then filtered.
• the liquid phase is isolated and the residue is dissolved in 150 ml of water.
• the solution is run under continuous stirring into 3 l of ethanol containing 5% of water.
• the flocculent precipitate is filtered off and dried. The reprecipitation is repeated twice in the described manner.
• the oily part containing solid substance is washed twice with 50 ml of acetone each, then it is dissolved in 170 ml of water and the solution is dropped to a mixture of acetone and ethanol (1700 ml) in a ratio of 1:1. the orange-coloured precipitate is filtered off, washed with ethylacetate, then with ether and finally dried in vacuo. Weight: 18 g.
• the substance is dissolved in 120 ml of distilled water and the solution is poured into 1200 ml of a mixture of acetone and ethanol in a ratio of 2:1. 14.5 g of precipitate are obtained which are washed and dried in the described manner. The reprecipitation is repeated three times.
• the precipitate is dissolved in 270 ml of distilled water, the solution is added drop by drop to 2700 ml of dry ethanol and in order to promote the precipitate formation some common salt solution is added. The described reprecipitation is repeated twice. 24.2 g (51.35%) of product are obtained.
• FIG. 1 shows the carbon spectrum ( 13 C-NMR) of the starting substance 3,6-diamino-10-methyl-acridinium-chloride
• FIG. 2 the same spectrum of the final product substituted by glucose in positions 3 and 6 at the amino group.
• the chemical shift of the carbon atoms of the sugar part is a proof for the pyranose structure of the glycoside while the coupling constants 1 J C .sbsb.1 -H .sbsb.1 support the given anomer configuration. (The spectra were taken in DMSO-d 6 .)
• the precipitate consists of mono- and digalactoside in a ratio of 1:4. Under slight heating the precipitate is dissolved in 60 ml of water and the solution is dropped into 700 ml of ethanol under stirring. The mixture is reacted with 2 ml of a 10 percent sodium chloride solution and then left to stand. The solid substance is filtered off, washed with some alcohol at first, then with ethylacetate and finally with ether, then it is dried in a vacuum desiccator. 7.4 g of product are obtained which contains unreacted starting substance practically no more and monoglycoside in a quantity of about 10-15%. The 4.9 g of substance obtained after three repeated reprecipitations contains still 5-10 g of monogalactoside as shown by the 13 C-NMR-spectrum.
• the precipitate is now dissolved in 40 ml of warm water and then acetone is added (about 60 l) drop by drop until precipitation begins. This reprecipitation is repeated three times, too.
• the thus-obtained product consists of pure dirhamnoside.
• Example 12 The filtrates of the reprecipitations described in Example 12 are united and under stirring they are poured into 200 ml of acetone whereupon the monorhamnoside is separated. The substance is filtered off, dissolved in water and lyophilized.
• a suspension of 2.60 g (10 -2 mole) of 3,6-diamino-10-N-methyl-acridine in 100 ml of a mixture of ethanol and water in a ratio of 7:3 is reacted with 0.2 ml of concentrated hydrochloric acid and then boiled until the solution becomes clear.
• After adding 5.40 g (1.5 ⁇ 10 -2 mole) of lactose-monohydrate the reaction mixture is stirred at boiling temperature for an hour and then at room temperature for a night.
• the separated precipitate is filtered off and under slight heating it is dissolved in 30 ml of water.
• the solution is dropped into 300 ml of ethanol under stirring. The reprecipitation is repeated.

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